MIR148A family regulates cardiomyocyte differentiation of human embryonic stem cells by inhibiting the DLL1-mediated NOTCH signaling pathway

Abstract

MicroRNAs (miRNAs), as a class of naturally occurring RNAs, play important roles in cardiac physiology and pathology. There are many miRNAs that show multifarious expression patterns during cardiomyocyte genesis. Here, we focused on the MIR148A family, which is composed of MIR148A, MIR148B and MIR152, and shares the same seed sequences. The expression levels of all MIR148A family members progressively increased during the differentiation of human embryonic stem cells (hESCs) into cardiomyocytes. The deletion of MIR148A family (MIR148A-TKO) resulted in a decreased proportion of cardiomyocytes after cardiac induction, which was restored by the ectopic expression of MIR148A family members. Transcriptome analyses indicated that the MIR148A family could partially repress paraxial mesodermal differentiation from primitive streak cells. In turn, these miRNAs promoted lateral mesoderm and cardiomyocyte differentiation. Furthermore, the NOTCH ligand Delta-like 1 (DLL1) was validated as the target gene of MIR148A family, and knockdown of DLL1 could promote the cardiomyocyte differentiation of MIR148A-TKO hESCs. Thus, our results demonstrate MIR148A family could promote cardiomyocyte differentiation by inhibiting undesired paraxial mesoderm lineage commitment, which improves our understanding on cardiomyocyte differentiation from hESCs.